Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC

Safety of third dose of COVID-19 vaccination in frail patients: Results from the prospective Italian VAX4FRAIL study

Importance: Despite people with impaired immune competence due to an underlying disease or ongoing therapy, hereinafter frail patients, are (likely to be) the first to be vaccinated, they were usually excluded from clinical trials. Objective: To report adverse reactions of frail patients after receipt of the third dose (booster) administered after completion of a two-dose mRNA vaccination and to compare with those reported after the receipt of the first two doses. Design: A multicenter, observational, prospective study aimed at evaluating both the safety profile and the immune response of Pfizer-BioNTech or Moderna vaccines in frail patients. Setting: National Project on Vaccines, COVID-19 and Frail Patients (VAX4FRAIL) Participants: People consenting and included in the VAX4FRAIL trial. Exposure: A series of three doses of COVID-19 mRNA vaccination from the same manufacturer. Main outcome(s) and measure(s): Evaluation of a self-assessment questionnaire addressing a predefined list of eight symptoms on a five-item Likert scale. Symptoms were classified as severe if the patient rated them as severe or overwhelming. Results: Among 320 VAX4FRAIL participants diagnosed/treated for hematological malignancies (N=105; 32.8%), solid tumors (N=48; 15.0%), immune-rheumatological diseases (N=60; 18.8%), neurological diseases (N=107; 33.4%), and receiving the booster dose, 70.3% reported at least one loco-regional or systemic reactions. Adverse events were mostly mild or moderate, none being life-threatening. Only six of the 320 (1.9%) patients had their treatment postponed due to the vaccine. The safety profile of the booster compared to previously administered two doses showed a stable prevalence of patients with one or more adverse events (73.5%, 79.7% and 73.9% respectively), and a slightly increment of patients with one or more severe adverse events (13.4%, 13.9% and 19.2% respectively). Conclusions and relevance: The booster of the mRNA COVID-19 vaccine was safely administered in the largest prospective cohort of frail patients reported so far. VAX4FRAIL will continue to monitor the safety of additional vaccine doses, especially systemic adverse events that can be easily prevented to avoid interruption of continuity of care. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04848493, identifier NCT04848493

FOLFIRINOX after first-line gemcitabine-based chemotherapy in advanced pancreatic cancer: a retrospective comparison with FOLFOX and FOLFIRI schedules

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear. Methods: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes. Results: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks (p = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks versus 23.07 weeks) or OS2 (47.86 weeks versus 42.00 weeks). The most common grade 3–4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups. Conclusion: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen

The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib

Background and aims The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Methods This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). Results A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12–76.3) and 6.8 months (95% CI 2.7–24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. Conclusions PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC

ESPaR. Il manuale

L\u2019obiettivo di questo manuale \ue8 quello di condividere obiettivi, struttura e dettagli del modello di bilancio di competenze per richiedenti asilo e rifugiati politici denominato \u201cESPaR\u201d. I primi due capitoli sono dedicati ai bisogni di orientamento formativo e professionale dei migranti e ai punti di attenzione da tenere in considerazione quando si fa consulenza di carriera con questo specifico target. \uc8 una parte molto importante del manuale perch\ue9 permette di cogliere il senso del modello ESPaR: chi fino ad oggi ha avuto la possibilit\ue0 di conoscerlo l\u2019ha considerato innovativo non tanto perch\ue9 propone interventi mai sperimentati in precedenza, ma perch\ue9 intende agire su dinamiche di conoscenza e maturazione personale quasi sempre bypassate dai classici interventi di supporto all\u2019inserimento lavorativo che riguardano i migranti ma non solo. Il terzo capitolo propone un focus sulla consulenza multiculturale, evidenziando che questa non si pu\uf2 fondare solo su un generico atteggiamento di accoglienza dell\u2019altro, ma che necessita anche di competenze specifiche. Seguono due capitoli metodologici dedicati, dei quali il primo \ue8 dedicato alla narrazione autobiografica, che \ue8 alla base di tutto il percorso. Durante lo svolgimento di quest\u2019ultimo, la narrazione passa da una modalit\ue0 meno strutturata, finalizzata ad una prima presa di coscienza delle proprie caratteristiche, all\u2019elaborazione del lutto per la perdita della propria professionalit\ue0 e allo sviluppo del giusto atteggiamento verso la riprogettazione di carriera, ad una modalit\ue0 pi\uf9 strutturata, dalla quale consegue una maggiore convinzione delle proprie competenze e motivazioni ed una migliore capacit\ue0 di presentarsi sul mercato del lavoro. Il secondo capitolo \ue8 invece dedicato all\u2019orientamento di gruppo, al fine di garantire che i singoli incontri, che sono condotti principalmente in questa forma, possano essere quanto pi\uf9 possibile efficienti. Conclusa la parte di introduzione teorica, viene presentato il modello, dedicando uno specifico paragrafo ad ogni intervento. Al suo interno \ue8 possibile visionare le immagini delle schede predisposte per alcune delle attivit\ue0 previste, mentre si rimanda ad internet per poter accedere al materiale da stampare per il suo utilizzo durante la conduzione dei gruppi. L\u2019ultimo capitolo \ue8 dedicato alla sperimentazione, che \ue8 stata condotta nell\u2019estate del 2017, la cui valutazione ha permesso di ottimizzare l\u2019intervento rendendolo cos\uec pi\uf9 efficiente ed efficace

ESPaR. The manual

The aim of this manual is to share the objectives, structure and details of the skills profile model for asylum seekers and political refugees called \u201cESPaR\u201d. The first two chapters are dedicated to the need for training and professional orientation of migrants and to the points of attention taken into account when making career counselling with this specific target. It is a really important part of the manual that allows to grasp the meaning of the ESPaR model: who got the opportunity to get in touch with it, has considered it innovative not so much because it proposes interventions that have never been experienced before, as because it intends to act on the dynamics of knowledge and personal improvement often eluded by interventions to support job placement not only concerning migrants. The third chapter suggests a focus on the multicultural counselling, pointing out that it cannot be based only on a general reception attitude, but it needs specific skills. Two methodological chapters follow; the first is dedicated to the autobiographical narration, which is the basis of the whole path. During this chapter, the narration moves from a less structured modality, aimed at a first awareness of their own characteristics to the grieving process for the loss of their own professionalism and to the development of the right attitude towards the new career planning, in a more structured way which results in a greater conviction of their skills and motivations and a better ability to present themselves on the labour market. The second chapter is instead dedicated to group orientation, in order to guarantee the individual meetings, mainly conducted in this form, to be as efficient as possible. Once the theoretical intro is over, the model is introduced by dedicating a specific paragraph to each intervention. In it, you can view the images of the information sheets for some of the planned activities, while internet is used as a reference to access the material to be printed during the conduct of the groups. The last chapter is dedicated to experimentation, which was conducted in the summer of 2017, the evaluation of which allowed optimizing the intervention making it more efficient and effective